Magnetic Entropy as a Proposed Gating Mechanism for Magnetogenetic Ion Channels

Abstract

Magnetically sensitive ion channels would allow researchers to better study how specific brain cells affect behavior in freely moving animals; however, recent reports of ''magnetogenetic'' ion channels based on biogenic ferritin nanoparticles have been questioned because known biophysical mechanisms cannot explain experimental observations. Here, we reproduce a weak magnetically mediated calcium response in HEK cells expressing a previously published TRPV4-ferritin fusion protein. We find that this magnetic sensitivity is attenuated when we reduce the temperature sensitivity of the channel but not when we reduce the mechanical sensitivity of the channel, suggesting that the magnetic sensitivity of this channel is thermally mediated. As a potential mechanism for this thermally mediated magnetic response, we propose that changes in the magnetic entropy of the ferritin particle can generate heat via the magnetocaloric effect and consequently gate the associated temperature-sensitive ion channel. Unlike other forms of magnetic heating, the magnetocaloric mechanism can cool magnetic particles during demagnetization. To test this prediction, we constructed a magnetogenetic channel based on the cold-sensitive TRPM8 channel. Our observation of a magnetic response in cold-gated channels is consistent with the magnetocaloric hypothesis. Together, these new data and our proposed mechanism of action provide additional resources for understanding how ion channels could be activated by low-frequency magnetic fields.

Uncovering a possible role of reactive oxygen species in magnetogenetics

“…While several groups have reproduced the key observation that a sufficiently strong magnetic field can gate TRPV1 [15][16][17] and TRPV4 18,42 , some theoretical calculations have questioned whether ferritin's magnetic properties are sufficient to actuate the channels by either localized heating or mechanical force 24 , as has been proposed. Additionally, follow-up studies of the TRPV4-ferritin platform by Wang et al 43 , Xu et al 44 , and Kole et al 45 , all using electrophysiological readouts, have been unsuccessful in recapitulating the results by Wheeler et al 18 , leading others to suggest alternative physical mechanisms that may account for the growing body of empiric data 42,46,47 . However, none of these studies proposed a possible chemical mechanism, a possibility that was tested here using chemical inhibitors or quenchers of reactive oxygen species generation.…”

Revaluation of magnetic properties of Magneto, MagR and αGFP−TRPV1/GFP−ferritin

“…Notably, Wheeler et al used the recorded action potentials as the primary evidence to argue that Magneto2.0 serves as a magnetic actuator (and its surface expression) 2 , yet these electrophysiology recordings were poorly controlled and confounded by spontaneous action potentials. Thus, the rigorous electrophysiology experiment that is essential for validating Magneto as a magnetic actuator remains missing (also see 11 with data suggestive of the endoplasmic reticulum as the source of minimal intracellular Ca 2+ elevation). Indeed, with the location of stimulating magnets continuously monitored, multiple independent electrophysiological experiments in this study (some using the exact same magnetic stimulations and/or tissues prepared for Wheeler et al), together with those in the two accompanied studies 9,10 , consistently demonstrated that Magneto did not respond to magnetic stimuli with any membrane depolarization (let alone action potential firing).…”

Stable behavioral and neural responses to thermal stimulation despite large changes in theHydra vulgarisnervous system

“…The master mold for the flow layer (adapted from Duret et al [32]) was 3D-printed with 1mm tall channels (Form 2, Flexible Resin, Formlabs). After curing the PDMS for the bottom flow layer (thereby embedding the immobilization chamber), holes were punched for inlet/outlet access for the flow layer.…”